The “gene dosage effect” hypothesis versus the “amplified developmental instability” hypothesis in Down syndrome

  • M. A. Pritchard
  • I. Kola
Conference paper


Two hypotheses exist to explain the Down syndrome (DS) phenotype. The “gene dosage effect” hypothesis states that the phenotype is a direct result of the cumulative effect of the imbalance of the individual genes located on the triplicated chromosome or chromosome region. In a nut shell, the phenotype results directly from the overexpression of specific chromosome 21 genes. The “amplified developmental instability” hypothesis contends that most manifestations of DS may be interpreted as the results of a non-specific disturbance of chromosome balance, resulting in a disruption of homeostasis. This hypothesis was proposed in an attempt to explain the similarities between the phenotypes of different aneuploid states and the observation that all of the phenotypic traits in DS are also seen in the general population but at lower frequency, with less severity and usually only present as a single trait. Herein, we review recent data and present evidence to support the theory that the phenotypic traits of aneuploid syndromes, and DS in particular, result from the increased dosage of genes encoded on the triplicated chromosome.


Down Syndrome Klinefelter Syndrome Gene Dosage Effect Developmental Instability Ts65Dn Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahlbom BE, Goetz P, Korenberg JR, Pettersson U, Seemanova E, Wadelius C, Zech L, Anneren G (1996) Molecular analysis of chromosome 21 in a patient with a pheno-type of Down syndrome and apparently normal karyotype. Am J Med Genet 63: 566–572PubMedCrossRefGoogle Scholar
  2. Barden HS (1980) Fluctuating dental asymmetry: a measure of developmental instability in Down syndrome. Am J Phys Anthropol 52: 169–173PubMedCrossRefGoogle Scholar
  3. Blum-Hoffmann E, Rehder H, Langenbeck U (1988) Skeletal anomalies in trisomy 21 as an example of amplified developmental instability in chromosome disorders: a histological study of the feet of 21 mid-trimester fetuses with trisomy 21. Am J Med Genet 29: 155–160PubMedCrossRefGoogle Scholar
  4. Breg WR (1977) Down syndrome: a review of recent progress in research. Pathobiol Annu 7: 257–303PubMedGoogle Scholar
  5. Caviedes P, Ault B, Rapoport SI (1990) Electrical membrane properties of cultured dorsal root ganglion neurons from trisomy 19 mouse fetuses: a comparison with the trisomy 16 mouse fetus, a model for Down syndrome. Brain Res 511: 169–172PubMedCrossRefGoogle Scholar
  6. Coussons-Read ME, Crnic LS (1996) Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: altered behavior in the elevated plus maze and open field. Behav Genet 26: 7–13PubMedCrossRefGoogle Scholar
  7. Davisson MT, Schmidt C, Reeves RH, Irving NG, Akeson EC, Harris BS, Bronson RT (1993) Segmental trisomy as a mouse model for DS. In: Epstein CJ (ed) The pheno-typic mapping of Down syndrome and other aneuploid conditions. John Wiley, New York, pp 117–133Google Scholar
  8. Dunlap SS, Aziz MA, Rosenbaum KN (1986) Comparative anatomical analysis of human trisomies 13, 18 and 21: the forelimb. Teratology 33: 159–186PubMedCrossRefGoogle Scholar
  9. Epstein CJ (1986) The consequences of chromosome imbalance: principles, mechanisms and models. Cambridge University Press, New YorkCrossRefGoogle Scholar
  10. Epstein CJ (1988) Specificity versus nonspecificity in the pathogenesis of aneuploid phenotypes. Am J Med Genet 29: 161–165PubMedCrossRefGoogle Scholar
  11. Escorihuela RM, Fernández-Teruel A, Vallina IF, Baamonde C, Lumbreras MA, Dierssen M, Tobeña A, Flórez J (1995) Behavioral assessment of Ts65Dn mice: a putative DS model. Neurosci Lett 199: 143–146PubMedCrossRefGoogle Scholar
  12. Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW (1989) Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr 114: 79–86PubMedCrossRefGoogle Scholar
  13. Gearhart JD, Davisson MT, Oster-Granite ML (1986) Autosomal aneuploidy in mice: generation and developmental consequences. Brain Res Bull 16: 789–801PubMedCrossRefGoogle Scholar
  14. Greber-Platzer S, Schatzmann-Turhani D, Wollenek G, Lubec G (1999) Evidence against the current hypothesis of “gene dosage effects” of trisomy 21: Ets-2, encoded on chromosome 21 is not overexpressed in hearts of patients with Down Syndrome. Biochem Biophys Res Commun 254: 395–399PubMedCrossRefGoogle Scholar
  15. Hassold TJ, Jacobs PA (1984) Trisomy in man. Annu Rev Genet 18: 69–97PubMedCrossRefGoogle Scholar
  16. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, Johnson RM, Chen K, Sun Y, Carlson E, Alleva E, Epstein CJ, Mobley WC (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of DS. Proc Natl Acad Sci USA 93: 13333–13338PubMedCrossRefGoogle Scholar
  17. Jones KL (ed) (1988) Smith’s recognizable patterns of human malformation, 4th ed. WB Saunders, PhiladelphiaGoogle Scholar
  18. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Eisen H, Childs B, Kazanian HH, Kucherlapati R, Atonarakis SE, Pulver AE, Housman (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 92: 7612–7616PubMedCrossRefGoogle Scholar
  19. Kola I, Hertzog P (1997) Animal models in the study of the biological function of genes on HSA21 and their role in the pathophysiology of DS. Hum Mol Genet 6:1713–1727PubMedCrossRefGoogle Scholar
  20. Kola I, Herzog PJ (1998) Down Syndrome in mouse models. Curr Opin Genet Dev 8: 316–321PubMedCrossRefGoogle Scholar
  21. Kola I, Pritchard M (1999) Animal models of Down syndrome. Mol Med Today 5: 276–277PubMedCrossRefGoogle Scholar
  22. Korenberg JR, Bradley C, Disteche CM (1992) Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 50: 294–302PubMedGoogle Scholar
  23. Kurnit DM, Aldridge JF, Matsuoka R, Matthysse S (1985) Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in Down syndrome: a stochastic model. Am J Med Genet 30: 385–399CrossRefGoogle Scholar
  24. Langenbeck U, Blum E, Wilkert-Walter C, Hansmann (1984) Developmental pathogenesis of chromosome disorders: report on two newly recognized signs of Down syndrome. Am J Med Genet 18: 223–230PubMedCrossRefGoogle Scholar
  25. Lee LG, Jackson JF (1972) Diagnosis of Down’s syndrome: clinical versus laboratory. Clin Pediatr 11: 353–356CrossRefGoogle Scholar
  26. Li J, Xu M, Zhou H, Ma J, Potter H (1997) Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 90: 917–927PubMedCrossRefGoogle Scholar
  27. Mueller RF, Young ID (1998) Chromosome disorders. In: Emery’s Elements of Medical Genetics. Churchill Livinstone, pp 245–264Google Scholar
  28. Opitz J (1982) The developmental field concept in clinical genetics. J Pediatr 101: 805–809PubMedCrossRefGoogle Scholar
  29. Oster-Granite ML, Lacey-Casem ML (1995) Neurotransmitter alterations in the trisomy 16 mouse: a genetic model system for studies of Down syndrome. MRDD Res Rev 1: 227–236Google Scholar
  30. Paoloni-Giacobino A, Chen H, Antonarakis SE (1997) Cloning of a novel human neural cell adhesion molecule gene (NCAM2) that maps to chromosome region 21q21 and is potentially involved in Down syndrome. Genomics 43: 43–51PubMedCrossRefGoogle Scholar
  31. Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC (1998) Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol 43: 380–383PubMedCrossRefGoogle Scholar
  32. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmid C, Bronson RT, Davisson M (1995) A mouse model for DS exhibits learning and behaviour deficits. Nat Genet 11: 177–184PubMedCrossRefGoogle Scholar
  33. Sago H, Carlson EJ, Smith D, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang TT (1998) TslCje, a partial trisomy 16 mouse model for DS, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA 95: 6256–6261PubMedCrossRefGoogle Scholar
  34. Sakata K, Tamura G, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, Terashima M, Saito K, Satodate R (1997) Commonly deleted regions on the long arm of chromosome 21 in differentiated adenocarcinoma of the stomach. Genes Chromosomes Cancer 18: 318–321PubMedCrossRefGoogle Scholar
  35. Satge D, Sasco AJ, Geneix A, Malet P (1998a) Another reason to look for tumor suppressor genes on chromosome 21. Genes Chromosomes Cancer 21: 1PubMedCrossRefGoogle Scholar
  36. Satge D, Sasco AJ, Carlsen NL, Stiller CA, Rubie H, Hero B, de Bernardi B, de Kraker J, Coze C, Kogner P, Langmark F, Hakvoort-Cammel FG, Beck D, von der Weid N, Parkes S, Hartmann O, Lippens RJ, Kamps WA, Sommelet D (1998b) A lack of neuroblastoma in Down syndrome: a study from 11 European countries. Cancer Res 58: 448–452PubMedGoogle Scholar
  37. Shapiro BL (1975) Amplified developmental instability in Down’s syndrome. Ann Hum Genet 38: 429–437PubMedCrossRefGoogle Scholar
  38. Shapiro BL (1983) Down syndrome-A disruption of homeostasis. Am J Med Genet 14: 241–296PubMedCrossRefGoogle Scholar
  39. Shapiro BL (1989) The pathogenesis of aneuploid phenotypes: the fallacy of explanatory reductionism. Am J Med Genet 33: 146–150PubMedCrossRefGoogle Scholar
  40. Shapiro BL (1994) The environmental basis of the Down syndrome phenotype. Dev Med Child Neurol 36: 84–90PubMedCrossRefGoogle Scholar
  41. Shen JJ, Williams BJ, Zipursky A, Doyle J, Sherman SL, Jacobs PA, Shugar AL, Soukup SW, Hassold TJ (1995) Cytogenetic and molecular studies of Down syndrome individuals with leukemia. Am J Hum Genet 56: 915–925PubMedGoogle Scholar
  42. Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O’Dell TJ, Fung J, Weier HU, Cheng JF, Rubin EM (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat Genet 16: 28–36PubMedCrossRefGoogle Scholar
  43. Trauner DA, Bellugi U, Chase C (1989) Neurologic features of Williams and Down syndromes. Pediatr Neurol 5: 166–168PubMedCrossRefGoogle Scholar
  44. Wilson L, Curtis A, Korenberg JR, Schipper RD, Allan L, Chenevix-Trench G, Stephenson A, Goodship J, Burn J (1993) A large, dominant pedigree of atrioventricular septal defect (AVSD): exclusion from the Down syndrome critical region on chromosome 21. Am J Hum Genet 53: 1262–1268PubMedGoogle Scholar
  45. Witkop CJ Jr, Keenan KM, Cervenka J, Jaspers MT (1988) Taurodontism: an anomaly of teeth reflecting disruptive developmental homeostasis. Am J Med Genet [Suppl]4: 85–97CrossRefGoogle Scholar
  46. Yamakawa K, Huot YK, Haendelt MA, Hubert R, Chen XN, Lyons GE, Korenberg JR (1998) DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. Hum Mol Genet 7: 227–237PubMedCrossRefGoogle Scholar
  47. Zihni L (1994) Down’s syndrome, interferon sensitivity and the development of leukaemia. Leuk Res 18: 1–6PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • M. A. Pritchard
    • 1
  • I. Kola
    • 1
    • 2
  1. 1.Centre for Functional Genomics and Human Disease, Institute of Reproduction and DevelopmentMonash UniversityClaytonAustralia
  2. 2.Centre for Functional Genomics and Human Disease, Institute of Reproduction and DevelopmentMonash Medical CentreClaytonAustralia

Personalised recommendations